Method for preparing 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease

ABSTRACT

A method is provided for preparing 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A 2  (TXA 2 ) receptor antagonists or combined thromboxane A 2  receptor antagonists/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic disease, wherein a vinyl bromide of the formula, for example, ##STR1## wherein m, n, R 1  and R 2  are as defined herein is treated with a cyclizing agent to form the corresponding oxazole.

This is a continuation-in-part of application Ser. No. 846,842, filedMar. 6, 1992, now abandoned.

DESCRIPTION OF THE INVENTION

The present invention relates to a method for preparing7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogswhich are thromboxane A₂ (TXA₂) receptor antagonists or combinedthromboxane A₂ receptor antagonists/thromboxane synthetase inhibitorsuseful, for example, in the treatment of thrombotic and/or vasospasticdisease, and described in U.S. application Ser. No. 540,026, filed Jun.18, 1990 now U.S. Pat. No. 5,100,889, issued Mar. 31, 1991 (which isincorporated herein by reference), and to a method for preparingintermediates for use in the above method.

In accordance with the present invention, a method is provided forpreparing oxazoles of the structure I ##STR2## and including allstereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

(CH₂)_(n) is unsubstituted or substituted with one or two lower alkylgroups;

R is CO₂ H, CO₂ lower alkyl or CO₂ alkali metal;

R¹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl,aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or amide ##STR3##wherein t is 1 to 12 and R_(a) is lower alkyl, aryl, cycloalkyl, orcycloalkylalkyl), each of R¹ being unsubstituted or optionallysubstituted with a lower alkyl, aryl, cycloalkyl, or cycloalkylalkylgroup;

R² is hydrogen, lower alkyl, aryl, or aralkyl; or

R¹ and R² together with the nitrogen to which they are linked may form a5- to 8- membered ring;

wherein a vinyl bromide of the structure ##STR4## is treated with acyclizing agent, such as a metal carbonate, for example, cesiumcarbonate, in the presence of an inert organic solvent, such as dioxaneto form the desired oxazole ester I wherein R is CO₂ alkyl.

The oxazole ester may be converted to the corresponding alkali metalsalt such as sodium, potassium or lithium salt, preferably the sodiumsalt, by treating oxazole I wherein R is CO₂ alkyl with an alkali metalhydroxide to form the alkali metal salt.

The oxazole salt may then be converted to the free acid by treating thesalt with an acid such as hydrochloric acid or oxalic acid.

In addition, in accordance with the present invention, a method isprovided for preparing oxazoles of formula I wherein an amide of thestructure ##STR5## wherein m, n, R, R¹ and R² are as defined above istreated with a bromine source such as Br₂ or N-bromosuccinamide followedby treatment with an amine base, such as triethylamine, at a reducedtemperature, under an inert atmosphere, such as argon, and then istreated with an organic base to form the bromo-ester compound II, whichis then employed as described above to form oxazole I.

Further in accordance with the present invention, a method is providedfor preparing oxazoles of formula I wherein a chloromethyl amide of thestructure IV ##STR6## wherein m, n, R¹ and R² are as defined above, istreated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an inertatmosphere, such as argon, to form the amide III, which is then employedas described above to form oxazole I.

Still further in accordance with the present invention, a method isprovided for forming the starting chloromethyl amide IV wherein ahydroxymethyl compound of the structure V ##STR7## is treated withmethanesulfonyl chloride (mesyl chloride) in the presence of an organicbase to form the mesylate VI ##STR8## and mesylate VI is subjected to adisplacement reaction wherein VI is treated with an alkali metal saltsuch as lithium chloride or a quaternary ammonium salt such asbenzyltributyl ammonium chloride, to form the chloromethyl amide IV.

In an alternative method for preparing the starting chloromethyl amideIV, in accordance with the present invention, an amide of the structureVII (formed from the corresponding amine VIIA) ##STR9## wherein Prorepresents a protecting group, and R¹ and R² are as defined above, istreated with an organic base and methanesulfonyl chloride at a reducedtemperature to form the mesylate VIII. ##STR10## Mesylate VIII issubjected to a displacement reaction wherein VIII is treated with analkali metal salt such as lithium chloride or a quaternary ammonium saltsuch as benzyltributyl ammonium chloride, at an elevated temperature toform chloromethyl compound IX ##STR11## chloromethyl compound IX istreated with a deprotecting agent to form the chloromethyl amine X##STR12## and X is coupled with acid XI ##STR13## in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) ordicyclohexylcarbodiimide (DCC), and 1-hydroxybenzotriazole (HOBT), inthe presence of N-methylmorpholine (NMM), to form the chloromethylamideIV.

Alternatively, the acid XI can be converted to the corresponding acidchloride by treatment with oxalyl chloride, preferably in the presenceof a catalytic amount of N,N-dimethylformamide, which acid chloride istreated with amine X in the presence of an acid scavanger such astriethylamine or DBU, or sodium bicarbonate (when employing aqueousconditions) to form chloromethylamide IV.

DETAILED DESCRIPTION OF THE INVENTION

In carrying out the present invention for preparing oxazoles I, vinylbromide II is treated with a metal carbonate cyclizing agent of thestructure A

    M.sub.2 CO.sub.3

where M is a Group 5 or 6 alkali metal, that is cesium or rubidum, or aGroup 5 or 6 alkaline earth metal, that is strontium or barium,preferably cesium, alone or optionally with a Group 2 to 4 alkali metalcarbonate, such as lithium carbonate, sodium carbonate or potassiumcarbonate, in the presence of an inert organic solvent such as dioxane,tetrahydrofuran (THF), ethyl acetate, toluene, or acetonitrile,preferably dioxane, at a temperature within the range of from about 25°to about 80° C., and preferably from about 30° to about 65° C. Thecyclizing agent A will be employed in a molar ratio to the vinyl bromideII of within the range of from about 0.75: to about 5:1, and preferablyfrom about 1:1 to about 3:1.

Preferred vinyl bromide starting materials will comprise those ofFormula II wherein m is 1 or 2 and n is 1, 2 or 3, R¹ is alkyl of from 3to 7 carbons and R² is hydrogen or alkyl of from 3 to 7 carbons.

Where the oxazole I is prepared starting with amide III, amide III willbe treated with a bromine source such as Br₂ or N-bromosuccinamide,preferably Br₂, at a reduced temperature of within the range of fromabout -80° to about -40° C., and preferably from about -80° to about-60° C., under an inert atmosphere such as argon or nitrogen, preferablyargon, employing a molar ratio of bromine source to amide III of withina range of from about 1:1 to about 2:1 and preferably from about 1:1 toabout 1.1:1. The organic base, which may be triethylamine, DBU, Hunig'sbase (diisopropylethyl amine), collidine, dimethylamino pyridine orpyridine, preferably triethylamine, will be admixed with the reactionmixture at a temperature of within the range of from about -78° C. toabout 25° C. and preferably from about -20° C. to about 0° C. The abovereactions will be carried out in the presence of an inert organicsolvent such as methylene chloride, chloroform, tetrahydrofuran (THF),acetonitrile, or acetone, preferably methylene chloride.

Where the oxazole I is prepared starting with the chloromethylamide IV,DBU will be employed in a molar ratio to amide IV of within the range offrom about 1:1 to about 4:1, preferably from about 1:1 to about 2:1, andthe reaction will be carried out under an inert atmosphere such as argonor nitrogen, preferably argon.

In a first method for preparing the starting chloromethyl amide IV,hydroxymethyl compound V (prepared as described in U.S. application Ser.No. 540,026, filed Jun. 18, 1990 now U.S. Pat. No. 5,100,889) will betreated with mesyl chloride employing a molar ratio of mesyl chloride toamide IV of within the range of from about 1:1 to about 3:1, andpreferably from about 1:1 to about 1.5:1, in the presence of an organicbase such as triethylamine or pyridine, preferably triethylamine, in thepresence of an inert organic solvent such as methylene chloride or THF,at a temperature of within a range of from about -78° C. to about 0° C.and preferably from about -20° C. to about 0° C.

The mesylate VI will be subjected to a displacement reaction bytreatment with an alkali metal salt such as lithium chloride, sodiumchloride, potassium chloride, lithium bromide or sodium iodide,preferably lithium chloride, or with a quaternary ammonium salt such asbenzyltributyl ammonium chloride, tetra-n-butylammonium bromide, ortetra-n-butylammonium iodide, employing a molar ratio of salt to VIwithin the range of from about 2:1 to about 10:1, preferably from about2:1 to about 5:1, the above reaction being carried out in the presenceof an inert organic solvent such as dimethylformamide, THF, acetone,chloroform or methylene chloride, preferably dimethylformamide ormethylene chloride.

In the alternative method for preparing the starting chloromethyl amideIV, the staring amide VII (prepared as described in U.S. applicationSer. No. 540,026, filed Jun. 18, 1990 now U.S. Pat. No. 5,100,889) willinclude a protecting group which can be t-butyloxycarbonyl (BOC) ortrichloroethoxy carbonyl, preferably BOC, and will be treated with anorganic base such as triethylamine, or pyridine, preferablytriethylamine, and methanesulfonyl chloride at a reduced temperature ofwithin the range of from about -78° C. to about 0° C. and preferablyfrom about -20° C. to about 0° C. to form the mesylate VIII. Themethanesulfonyl chloride will be employed in a molar ratio to amide VIIof within the range of from about 1:1 to about 5:1, preferably fromabout 1:1 to about 2:1.

The mesylated compound VIII will then be subjected to to a displacementreaction employing an alkali metal salt such as lithium chloride, sodiumchloride, potassium chloride, preferably lithium chloride, which isreacted with VIII at an elevated temperature of from about 40° C. toabout 100° C., and preferably from about 40° C. to about 65° C., to formthe chloromethyl compound IX. The alkali metal salt will be employed ina molar ratio to VIII of within the range of from about 2:1 to about10:1, preferably from about 2:1 to about 5:1.

The chloromethyl compound IX will be deprotected by reaction with adeprotecting agent such as trifluoroacetic acid, anhydrous hydrogenchloride or HCl/dioxane, preferably trifluoroacetic acid, employing amolar ratio of deprotecting agent to IX of within the range of fromabout 5:1 to about 20:1, preferably from about 5:1 to about 10:1 to formthe chloromethyl amine compound X.

Chloromethyl amine X is coupled with acid XI employing a molar ratio ofX:XI of within the range of from about 1:1 to about 3:1, preferably fromabout 1:1 to about 1.5:1. The coupling reaction is carried out in thepresence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(WSC) or dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole(HOBT) in the presence of N-methylmorpholine (NMM), employing a molarratio of WSC or DCC:XI of within the range of from about 1:1 to about3:1, preferably from about 1:1 to about 1.5:1. The HOBT will be employedin a molar ratio to WSC or DCC of within the range of from about 1:1 toabout 3:1, preferably from about 1:1 to about 1.5:1 while the NMM willbe employed in a molar ratio to HOBT of within the range of from about2:1 to about 5:1, preferably from about 2:1 to about 3:1. The abovereaction will be carried out at a temperature within the range of fromabout -20° C. to about 40° C. and preferably from about 0° C. to about25° C.

Alternatively, acid XI may be activated by forming a mixed anhydride,mixed carbonate, or preferably acid chloride (by known literaturemethods), using a slight excess (of from about 10 to about 50%) of amineand acid scavanger relative to the acid chloride. A reaction temperatureof from about -78° to about 0° C. will be employed.

The term "lower alkyl" or "alkyl" as employed herein includes bothstraight and branched chain radicals of up to 18 carbons, preferably 1to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1, 2 or 3 halo substituents, an aryl substituent, analkyl-aryl substituent, a haloaryl substituent, a cycloalkylsubstituent, an alkylcycloalkyl substituent, hydroxy or a carboxysubstituent.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groupscontaining 3 to 12 carbons, preferably 3 to 8 carbons, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may besubstituted with substituents such as halogen, lower alkyl, alkoxyand/or hydroxy group.

The term "aryl" or "Ar" as employed herein refers to monocyclic orbicyclic aromatic groups containing from 6 to 10 carbons in the ringportion, such as phenyl, naphthyl. Aryl (or Ar), phenyl or naphthyl mayinclude substituted aryl, substituted phenyl or substituted naphthyl,which may include 1 or 2 substituents on either the phenyl or naphthylsuch as lower alkyl, trifluoromethyl, halogen (Cl, Br, I or F), loweralkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl,arylthio, arylsulfinyl and/or arylsulfonyl.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinrefers to lower alkyl groups as discussed above having an arylsubstituent, such as benzyl.

The term "lower alkoxy", "alkoxy" or "aralkoxy" includes any of theabove lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herein refers to chlorine, bromine,fluorine or iodine with chlorine being preferred.

The term "lower alkenyl" or "alkenyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one double bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q) -- where q can be 1 to 14, such as 2-propenyl, 2-butenyl,3-butenyl, 2-pentenyl, 4-pentenyl and the like, and may include ahalogen substituent such as I, Cl, or F.

The term "lower alkynyl" or "alkynyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one triple bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q') -- where q' can be 1 to 14, such as 2-propynyl, 2-butynyl,3-butynyl and the like.

The term "cycloheteroalkyl" as used herein as an R¹ substitutent refersto a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms such as nitrogen, oxygen and/or sulfur, and which is linked to the"N" of the ##STR14## group through a carbon atom either beta or gamma toa heteroatom, such as ##STR15## and the like.

The term "heteroaryl" or heteroaromatic as an R¹ substitutent refers toa 5- or 6-membered aromatic ring which includes 1 or 2 hetero atoms suchas nitrogen, oxygen or sulfur, which are not directly linked through ahetero atom to the "N" of the ##STR16## group, such as ##STR17## and thelike

The term "cycloheteroalkylalkyl" as defined by R¹ refers to 5-, 6- or7-membered saturated ring which includes 1 or 2 heteroatoms such asnitrogen, oxygen or sulfur, and is linked to the "N" of the ##STR18##group through a (CH₂)_(x) chain wherein x is 1 to 12, preferably 1 to 8,such as ##STR19##

The term "heteroarylalkyl" as defined by R¹ refers to a 5-, 6- or7-membered aromatic ring which includes 1, 2, 3 or 4 heteroatoms such asnitrogen, oxygen or sulfur, and is linked to the "N" of the ##STR20##group through a --(CH₂)_(x') -- chain where x' is 1 to 12, preferably 1to 8, such as ##STR21##

Preferred compounds prepared in accordance with the method of theinvention are those compounds of formula I wherein m is 1, n is 1 or 2,R is CO₂ H, R¹ is substituted alkyl or a cycloheteroalkylalkyl and R² isH or lower alkyl, and --(CH₂)_(n) --CO₂ alkyl is in the ortho or metaposition.

The following examples represent preferred embodiments of the invention.

EXAMPLE 1 N-Pentyl-L-serinamide 1:1 oxalate salt AN-Pentyl-N2-[(phenylmethoxy)carbonyl]-L-serinamide

A 5-L, 3-necked flask was charged with N-CBZ-L-serine (110 g, 0.46 mole)(CBZ=carbobenzyloxy) followed by dichloromethane (2.1 L). The resultingslurry was stirred under argon and treated with triethylamine (61.7 mL,0.443 mole) over several minutes. The resulting hazy solution was cooledto an internal temperature of -35° and treated over 10 min withtrimethylacetylchloride (51.06 mL, 0.415 mole) such that the internaltemperature did not rise above -30°. The reaction was stirred anadditional 40 min at -25° to -30°, treated with pyridine (35.2 mL, 0.435mole) over 5 min and stirred an additional 10 min. Amylamine (51 mL,0.44 mole) was added over 10 min while maintaining the internaltemperature at -25° to -29°. The reaction was stirred for 30 min whilewarming to -25°. A precipitate formed during this warming. The reactionwas further warmed to -10° over 40 min during which time the precipitateredissolved. After stirring an additional 20 min at -10°, the reactionwas quenched by the addition of 500 mL of 1N HCl. The biphasic mixturewas stirred for 20 min and transferred to a separatory funnel. Theaqueous layer was extracted with dichloromethane (2×75 mL). The combineddichloromethane solutions were concentrated in vacuo to a weight of 500g. Ethyl acetate (EtOAc) (2.25 L) was added and the organic solution waswashed with 1N HCl (2×400 mL) and 1N K₂ CO₃ (1×700 mL and 2×500 mL). Theorganic solution was dried (magnesium sulfate), filtered andconcentrated in vacuo to the title compound which was used in the nextstep without purification.

B. N-Pentyl-L-serinamide, 1:1 oxalate salt

The part A compound was evaporated from 95% ethanol (EtOH) to removeresidual solvents. The residue was dissolved in 95% EtOH (1.28 L) andtreated under nitrogen with 20% Pd(OH)₂ (12.8 g). The mixture wasstirred and sparged with hydrogen. After 2.5 h the catalyst was filteredoff and washed with 95% EtOH. The filtrate was concentrated in vacuo to73.1 g. A portion of this material (36.3 g, 0.21 mole) was redissolvedin 95% EtOH (221 mL) and added slowly to a stirred room temperaturesolution of oxalic acid dihydrate (31.5 g, 0.25 mole) in 95% EtOH (221mL). After the addition the resulting slurry was further diluted with120 mL of 95% EtOH , stirred an additional 30 min and then heated toreflux. The slurry was treated with water (29 mL) to afford a clear,light yellow solution. After stirring an additional 40 min the heat wasremoved and the solution cooled. The resulting slurry was stirred atambient temperature for 18 h, filtered and washed with 95% EtOH (1×72mL, and 1×48 mL) and hexane (2×48 mL). Drying in vacuo produced 42.9 g(77.3%) of the title compound, mp 174° C.

EXAMPLE 2[1S-(1α,2α,3α,4α]-2-[[3-[4-[(Pentylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester A.[1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-(Hydroxymethyl)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of[1S-(1α,2α,3α,4α)]-2-[(3-carboxy-7-oxabicyclo[2.2.1]hept-2-yl)methyl]benzenepropanoicacid, methyl ester (prepared as described in U.S. Pat. No. 5,100,889)(17.6 g,.55.3 mmol) and 4-methylmorpholine (12.2 mL, 111 mmol) in 100 mLof DMF under argon at -10° C. was added dropwise isobutylchloroformate(7.94 mL, 61.2 mmol) over a 15 min period. This solution was stirred at-10° C. for 50 min at which time n-pentyl-L-serinamide (10.6 g, 57.5mmol) was added. The reaction mixture was stirred at -10° C. for 1 hourand at room temperature for 16 hours. This mixture was diluted with 2 Lof ethyl acetate (EtOAc) and washed with 1N HCl solution (2×600 mL),saturated NaHCO₃ solution (1×600 mL) and brine (1×600 mL). The EtOAclayer was dried (MgSO₄), filtered and concentrated in vacuo. This wastriturated in 600 mL of 1:1 ether-hexane to give 25.2 g (96%) of titleamide.

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.38, Cerium dip.

A¹. Alternative Procedure for Forming A

A solution of Part A acid ester starting material (30.27 g, 95.06 mmol)and DMF (1.5 mL, 19.37 mmol) in CH₂ Cl₂ (200 mL) was cooled to aninternal temperature of 0° C. under an argon atmosphere. To the abovesolution was added oxalyl chloride (9.1 mL, 104.57 mmol) over ˜2.5minutes. After 2 hours, gas evolution had ceased. A 75 μL aliquot wasremoved and quenched into MeOH. TLC analysis of this solution showed noremaining starting acid, thus indicating complete conversion to the acidchloride. Toluene (30 mL) was added to the reaction mixture. The crudeacid chloride solution was partially concentrated to an oil/solidmixture (43.37 g).

In a separate flask, a suspension of N-pentyl-L-serinamide oxalate salt(30.26 g, 114.50 mmol) in CH₂ Cl₂ (200 mL) was treated sequentially,under argon, with DBU (33.4 mL, 223.28 mmol) and Et₃ N (16.0 mL, 114.50mmol). The resulting solution was cooled to -78° C. The crude acidchloride was redissolved in CH₂ Cl₂ (350 mL), cooled to 8° C. underargon, and added to the solution of the amine via cannula such that thereaction temperature never exceeded -72° C. The addition processrequired 35 minutes. The flask containing the acid chloride solution wasrinsed with CH₂ Cl₂ (30 mL) which was transferred to the reactionmixture. After 45 minutes an aliquot was removed and quenched into MeOH.TLC analysis of the solution showed no evidence of unreacted acidchloride; only Part A title compound and a trace of starting acid werepresent. The dry ice/acetone bath was removed and with vigorousstirring, 1 N HCl (500 mL) was immediately added. The internaltemperature quickly rose to -10° C. After transferring to a separatoryfunnel, additional water (1 L) and CH₂ Cl₂ (250 mL) were added. Thelayers were mixed and split. The aqueous layer was extracted with CH₂Cl₂ (250 mL). The organic phases were combined and washed with 1N HCl(250 mL) and saturated aqueous NaHCO₃ (500 mL). The aqueous NaHCO₃solution was back-extracted with CH₂ Cl₂ (250 mL). The organic solutionswere combined, washed again with saturated aqueous NaHCO₃ (250 mL) andsaturated aqueous NaCl (500 mL), dried (MgSO₄), filtered, concentrated,and left under high vacuum for 12 hours to give the crude title compound(44.27 g).

A portion of this material (38.27 g) was placed in a flask with water(7.25 mL) and EtOAc (344 mL) and the mixture was brought to a boil. Theresulting clear yellow solution was allowed to cool to room temperatureand stand for 22 hours. EtOAc (125 mL) was added to slurry theall-engulfing white solid and the crystals were recovered viafiltration. The white crystals were washed sequentially with EtOAc (2×75mL) and hexanes (1×200 mL), air dried (1.5 hours), and placed under highvacuum for 24 hours to give the title compound (33.87 g).

Procedure I for B. and C. B.[1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-[[Methylsulfonyl)oxymethyl]-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester and C. [1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-(Chloromethyl)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of Part A amide (25.2 g, 53.2 mmol) in 480 mL ofdry CH₂ Cl₂ at -10° C. under argon was added, in order, triethylamine(Et₃ N) (8.88 mL, 63.8 mmol) and methanesulfonyl chloride (4.53 mL, 58.5mmol). This solution was stirred at -10° C. for 15 minutes and dilutedwith 200 mL of CH₂ Cl₂. This mixture was washed with ice-cold 1N HClsolution (2×150 mL) and a 1:1 mixture of saturated NaHCO₃ solution andbrine (1×150 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to give solid intermediate Part B mesylate. To astirred solution of this Part B mesylate in 120 mL of DMF was addedanhydrous lithium chloride (5.58 g, 133 mmol). An exotherm was noted.This solution was stirred at room temperature for 18 hours and thendiluted with 1 L of CH₂ Cl₂. The solution was washed with 10% LiClsolution (2×250 mL), water (2×250 mL), saturated NaHCO₃ solution (1×250mL) and brine (1×250 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo to give Part C chloride (26.2g, 100% crudeyield).

TLC: silica gel, 3:1 EtOAc-hexane, R_(f) 0.72, cerium dip. mp 180°-182°C.

[α]_(D) =-5.5° (c=0.9, CHCl₃).

Anal. Calc'd for C₂₆ H₃₇ N₂ O₅ Cl:

C, 63.34; H, 7.56; N, 5.68; Cl, 7.19

Found: C, 63.39; H, 7.68; N, 5.69; Cl, 7.36.

Alternative Procedure II for B. and C.

To a stirred solution of Part A amide (25.2 g, 53.2 mmol) in 250 mL ofdry CH₂ Cl₂ at -10° C. under argon is added, in order, triethylamine(Et₃ N) (8.88 mL, 63.8 mmol) and methanesulfonyl chloride (4.53 mL, 58.5mmol). This solution is stirred at -10° C. for 15 minutes and dilutedwith 100 mL of DMF. To this mixture is added anhydrous lithium chloride(5.58 g, 133 mmol) in 50 mL DMF. This solution is stirred at roomtemperature for 18 hours and then diluted with 1 L of CH₂ Cl₂. Thesolution is washed with 10% LiCl solution (2×250 mL), water (2×250 mL),saturated NaHCO₃ solution (1×250 mL) and brine (1×250 mL). The organiclayer is dried (MgSO₄), filtered and concentrated in vacuo to give PartC chloride.

Alternative Procedure III for B. and C.

To a stirred solution of Part A amide (25.2 g, 53.2 mmol) in 350 mL ofdry CH₂ Cl₂ at -10° C. under argon is added, in order, triethylamine(Et₃ N) (8.88 mL, 63.8 mmol) and methanesulfonyl chloride (4.53 mL, 58.5mmol). This solution is stirred at -10° C. for 15 minutes and dilutedwith 200 mL of CH₂ Cl₂. This mixture is washed with ice-cold 1N HClsolution (2×150 mL) and a 1:1 mixture of saturated NaHCO₃ solution andbrine (1×150 mL). The organic layer is dried (MgSO₄), filtered andconcentrated in vacuo to give solid intermediate Part B mesylate. To astirred solution of this Part B mesylate in 250 mL of CH₂ Cl₂portionwise is added benzyltributylammonium choride (33 g, 107 mmol).This solution is stirred at room temperature for 18 hours and thendiluted with 1 L of CH₂ Cl₂. The solution is washed with 10% LiClsolution (2×250 mL), water (2×250 mL), saturated NaHCO₃ solution (1×250mL) and brine (1×250 mL). The organic layer is dried (MgSO₄), filteredand concentrated in vacuo to give Part C chloride.

Alternative Procedure IV for B. and C.

To a stirred solution of Part A amide (25.2 g, 53.2 mmol) in 250 mL ofdry CH₂ Cl₂ at -10° C. under argon is added, in order, triethylamine(Et₃ N) (8.88 mL, 63.8 mmol) and methanesulfonyl chloride (4.53 mL, 58.5mmol). This solution is stirred at -10° C. for 15 minutes. To thismixture is added portionwise solid benzyltributylammonium chloride (33.0gm, 107 mmol). This solution is stirred at room temperature for 18 hoursand then diluted with 1 L of CH₂ Cl₂. The solution is washed with 10%LiCl solution (2×250 mL), water (2×250 mL), saturated NaHCO₃ solution(1×250 mL) and brine (1×250 mL). The organic layer is dried (MgSO₄),filtered and concentrated in vacuo to give Part C chloride.

D. [1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-Methylene-2-oxo-2-(pentylamino)ethylamino]carbonyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of Part C chloride (26.2 g, 53.2 mmol) in 740 mLof dry CH₂ Cl₂ under argon was added DBU (15.0 mL, 106 mmol). Thereaction mixture was stirred at room temperature for 4.5 hours andwashed with 1N HCl solution (2×400 mL), half-saturated NaHCO₃ solution(1×400 mL) and brine (1×400 mL). The organic layer was dried (MgSO₄),filtered and concentrated in vacuo to give 26 g of crude oil. This crudeoil (25 g) was chromatographed on 900 g of Merck silica gel 60 using 2 Lof 40% EtOAc in hexane and 6 L of 50% EtOAc in hexane as eluants to give17.4 g (72%) of title olefin as a viscous oil.

[α]_(D) =+27.7° (c=1.0, CH₃ OH).

TLC: silica gel, 2:1 EtOAc-hexane, R_(f) 0.64, cerium dip.

Anal. Calc'd for C₂₆ H₃₆ N₂ O₅ :

C, 68.40; H, 7.95; N, 6.14

Found: C, 68.10; H, 8.12; N, 5.87.

This olefin was stored at -78° C. under argon.

E.[1S-[1α,2α,3α(R*,E),4α]]-2-[[3-[[[1-(Bromomethylene)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-ylmethyl]benzenepropanoicacid, methyl ester and F.[1S-[1α,2α,3α(R*,Z),4α]]-2-[[3-[[[1-(Bromomethylene)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of purified Part D olefin (13.8 g, 30.3 mmol) in500 mL of dry CH₂ Cl₂ under argon at -78° C. was added bromine (1.58 mL,30.7 mmol). At the end of the addition of bromine the reaction mixturebecame bright yellow. This yellow solution was stirred at -78° C. for 15minutes and treated slowly with triethylamine (16.8 mL, 121 mmol). Thereaction flask was then transferred to a wet ice bath and stirred for 40minutes. The mixture was diluted with 200 mL of CH₂ Cl₂ and washed with2% NaHSO₃ solution (2×250 mL), water (1×250 mL) and brine (1×250 mL).The organic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was triturated with 1 L of 3:7 hexane-ether to give 14.9 g (92% or66% from starting methyl ester used in Part A) of 9:1 mixture of titlevinyl bromides E (major) and F (minor).

TLC: silica gel, 1:2 hexane-EtOAc, R_(f), 0.31, 0.56, UV & cerium dip.

HPLC: R_(T) =6.3 minutes (87%) and 7.2 minutes (9.5%), linear gradientof 72-90% aqueous methanol containing 0.2% H₃ PO₄, 20 minutes, detectedat 217 nm, YMC S-3 (ODS), 6.0×150 mm, 3 micron spherical end cappedcolumn, flow rate 1.5 mL/minute.

The product from a smaller scale reaction (1.9 mmol) was purified andseparated by chromatography on silica gel (150 mL, Merck), eluting withethyl acetate:hexane (1:1 and 1:2) and finally with ethyl acetate togive the two isomers E and F. The minor isomer F was obtained as a whitesolid (94 mg, 9.2%). mp. 104°-108° C.

[α]_(D) =+46.0° (c=0.7, CHCl₃).

Anal. Calc'd for C₂₆ H₃₅ N₂ O₅ Br:

C, 58.32; H, 6.59; N, 5.23, Br, 14.92

Found: C, 58.18; H, 6.66; N, 4.99; Br, 15.14.

The major isomer E was also a white solid (877 mg, 86%). mp. 160°-164°C.

[α]_(D) =-37.9° (c=1.0 CHCl₃).

Anal. Calc'd for C₂₆ H₃₅ N₂ O₅ Br:

C, 58.32; H, 6.59; N, 5.23; Br, 14.92

Found: C, 58.28; H, 6.64; N, 4.96; Br, 15.19.

Alternate E and F preparation

To a stirred solution of crude Part C olefin (olefin was worked up asdescribed in the above preparation and used without purification bycolumn chromatography, 1.10 g) in 42 mL of dry CH₂ Cl₂ under argon at-78° C. was added bromine over 10 minutes. Bromine was added until abright yellow color appeared and stayed in the reaction mixture. Theamount of bromine used in this scale was 125 μL. The mixture was stirredat -78° C. for 5 minutes and treated with Et₃ N (1.33 mL, 9.60 mmol).The reaction flask was then moved to a wet-ice bath and stirred for 30minutes. The mixture was diluted with 100 mL of CH₂ Cl₂ and washed with2% NaHSO₃ solution (2×60 mL), water (1×60 mL) and brine (1×60 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was triturated in 50 mL of ether to give 716 mg (57% from startingacids used in Part A) of a 9:1 mixture of vinyl bromides E and F.

TLC silica gel 1:2 hexane-EtOAc, R_(f), Part E compound, 0.31, Part Fcompound, 0.56, cerium dip.

TLC of the mother liquor indicated that the vinyl bromides were themajor components in this mixture.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Vinyl bromides E and F (3.21 g, 6 mmol, 1 eq., mixture of isomers) weredissolved in 1,4-dioxane (90 mL, Burdick and Jackson, stored overactivated sieves) and treated with cesium carbonate (3.17 g, 6 mmol, 1eq.) in an argon atmosphere. The mixture was stirred while heating in anoil bath maintained at 50°-53° C. for 23 hours. The reaction was cooledand diluted with ethyl acetate (400 mL). The ethyl acetate solution waswashed with water (100 mL) and saturated sodium chloride solution (100mL), dried (MgSO₄), and freed of solvent in vacuo leaving a semi-solid(3.40 g). This was stirred with ethyl ether (25 mL) for 1 hour and thencooled at -20° C. for 1 hour. Solid title oxazole was harvested byfiltration and washed with cold ether to give title compound, (1.346 g,49.4%), mp. 133°-136° C.

[α]_(D) =+15.4° (c=1.0, CHCl₃).

Anal Calc'd for C₂₆ H₃₄ N₂ O₅ :

C, 68.70; H, 7.54; N, 6.16

Found: C, 68.68; H, 7.73; N, 6.19.

HPLC: R_(T) =9.1 min., linear gradient of 72-90% aqueous methanolcontaining 0.2% H₃ PO₄, 20 min., detected at 217 nm, YMC S-3 (ODS),6.0×150 mm, 3 micron spherical end capped column, flow rate 1.5 mL/min.

Additional title oxazole (0.308 g, 11.3%) was obtained by silica gel(150 mL. Merck) column chromatography of the mother liquor (elutingsolvent--15% acetone in ethyl acetate).

EXAMPLE 3[1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-(Chloromethyl)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester A.(S)-[1-(Hydroxymethyl)-2-oxo-2-(pentylamino)ethyl]carbamic acid,1,1-dimethylethyl ester

N-Methylmorpholine (NMH) (2.2 g, 20 mmol) was added to a stirredsolution of N.sup.α -t-BOC-L-serine 4.12 g, 20 mmol), n-amylamine (2.25g, 25.9 mmol) and N-hydroxybenzotriazole (HOBT) (2.8 g, 20 mmol) indimethylformamide (DMF) (25 mL) at 0°-5° C. After a few minutes, WSC(3.8 g, 20 mmol) was added. The suspension was stirred at 0° C. to roomtemperature overnight. It was diluted with EtOAc (150 mL) and washedwith 1N aqueous HCl solution (30 mL, 2 times), aqueous sodiumbicarbonate solution (50 mL, 2 times), dried (MgSO₄), filtered andconcentrated to obtain title alcohol (4.85 g, 88% crude) as a lightyellow solid.

B.(S)-[1-[[(Methylsulfonyl)oxy]methyl]-2-oxo-2-(pentylamino)ethyl]carbamicacid, 1,1-dimethylethyl ester

Methanesulfonyl chloride (2.8 mL) was added dropwise to a stirredsolution of Part A alcohol (4.5 g, 16.42 mmol), triethylamine (1.54 mL,20 mmol) in dichloromethane (25 mL) at -10° C. After 30 minutes, themixture was diluted with ethyl acetate (EtOAc) (75 mL) and washed withwater (30 mL), 1N HCl solution (30 mL) and saturated brine (30 mL). TheEtOAc extract was dried (MgSO₄), filtered and concentrated to obtaintitle mesylate (5.25 g, 91% crude) as an off-white solid.

C. (R)-[1-(Chloromethyl)-2-oxo-2-(pentylamino)ethyl]carbamic acid,1,1-dimethylethyl, ester

A solution of Part B mesylate (5.2 g, 14.77 mmol) and anhydrous lithiumchloride (2 g, 47 mmol) in DMF (25 mL) was heated to 50°-52° C. for 30hours. The mixture was cooled to room temperature, diluted with EtOAc(100 mL) and washed with water (50 mL) and 10% aqueous LiCl solution (75mL, 2 times), dried (MgSO₄), filtered and concentrated to obtain titlechloromethyl compound (4.15 g, 96% crude) as a yellow oil.

D. (R)-2-Amino-3-chloro-N-pentylpropanamide

A solution of Part C chloromethyl compound (586 mg, 2 mmol) indichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred atroom temperature overnight. The mixture was concentrated under reducedpressure and the residual oil was dissolved in EtOAc (30 mL) and washedwith saturated NaHCO₃ solution (25 mL, 2 solution). The EtOAc extractwas dried (MgSO₄), filtered and concentrated to obtain title amine (300mg, 78% crude) as an oil.

E.[1S[1α,2α,3α(R*),4α]]-2-[[3-[[[1-(Chloromethyl)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

N-Methyl morpholine (151 mg, 1.5 mmol) was added to a stirred solutionof Part D amine (300 mg, 1.5 mmol),[1S-(1α,2α,3α,4α)]-2-[(3-carboxy-7-oxabicyclo[2.2.1]hept-2-yl)methyl]benzenepropanoicacid, methyl ester (477 g, 1.5 mmol) in DMF (15 mL) at 0°-5° C. After 5minutes, WSC (300 mg, 1.5 mmol) was added. The suspension was stirred at0° C. (2 hours) to room temperature overnight. It was diluted with EtOAc(50 mL) and washed with 1N aqueous HCl solution (30 mL. 2 times), 5%aqueous sodium bicarbonate solution (30 mL, 2 times), brine (30 mL),dried (MgSO₄), filtered and concentrated to obtain a solid which wasdiluted with ether (20 mL). The precipitated solid was filtered, washedwith ether and dried in vacuo to obtain title chloromethyl compound (455mg, 67%) as a white solid.

The so-formed chloromethyl compound may be employed to prepare oxazolesof formula I employing the procedure of Example 2.

Following the procedure of Example 2, the following acid and aminestarting material may be used employing procedures as described inExample 2 to prepare oxazoles I.

    ______________________________________                                         ##STR22##                  XI                                                 ##STR23##                  VIIA                                              XI            VIIA                                                            m   (CH.sub.2).sub.n n                                                                     (position)                                                                             R.sup.1        R.sup.2                                  ______________________________________                                        1   0        (2)      n-C.sub.4 H.sub.9                                                                            n-C.sub.4 H.sub.9                        2   1        (3)      C.sub.6 H.sub.5                                                                              H                                        1   2        (2)                                                                                     ##STR24##     H                                        2   3        (4)                                                                                     ##STR25##     H                                        3   4        (2)                                                                                     ##STR26##     H                                        1   1        (2)                                                                                     ##STR27##     H                                        2   2        (3)      C.sub.6 H.sub.13                                                                             CH.sub.3                                 3   3        (2)                                                                                     ##STR28##     CH.sub.3                                 2   0        (2)                                                                                     ##STR29##     H                                        3   1        (3)                                                                                     ##STR30##     H                                        2   2        (2)      C.sub.6 H.sub.5                                                                              C.sub.6 H.sub.5                          1   3        (3)      CH.sub.2 C.sub.6 H.sub.5                                                                     H                                        2   4        (2)      i-C.sub.3 H.sub.7                                                                            H                                        1   0        (2)                                                                                     ##STR31##     n-C.sub.4 H.sub.9                        2   1        (3)                                                                                     ##STR32##     H                                        3   2        (2)                                                                                     ##STR33##     CH.sub.2 C.sub.6 H.sub.5                 1   3        (3)      C.sub.2 H.sub.5                                                                              H                                        2   4        (2)                                                                                     ##STR34##     H                                        3   1        (3)      (CH.sub.2).sub.2 C.sub.6 H.sub. 5                                                            CH.sub.3                                 2   2        (2)      n-C.sub.3 H.sub.7                                                                            CH.sub.2 C.sub.6 H.sub.5                 3   3        (3)      n-C.sub.5 H.sub.11                                                                           H                                        2   0        (2)                                                                                     ##STR35##     CH.sub.3                                 1   2        (2)      (CH.sub.2).sub.6                                                              .BHorizBrace.                                           ______________________________________                                    

What is claimed is:
 1. A method for preparing an oxazole compound havingthe structure ##STR36## including all stereoisomers thereof, wherein mis 1, 2 or 3;n is 0, 1, 2, 3 or 4; (CH₂)_(n) is unsubstituted or issubstituted with one or two alkyl groups; R¹ is lower alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, saturated heterocycle, or aromaticheterocycle; and R² is hydrogen, lower alkyl, aryl, or aralkyl, or R¹and R² together with the N to which they are linked form a 5- to 8-membered ring; and which comprises treating a vinyl bromide of thestructure ##STR37## with a cyclizing agent which has the formula

    M.sub.2 CO.sub.3

wherein M is a Group 5 or 6 alkali metal or a Group 5 or 6 alkalineearth metal, to form the desired oxazole compound.
 2. The method asdefined in claim 1 wherein the cyclizing agent is a metal carbonate. 3.The method as defined in claim 1 wherein the cyclizing agent is employedin conjunction with a Group 2 to 4 alkali metal carbonate.
 4. The methodas defined in claim 3 wherein the Group 2 to 4 alkali metal carbonate islithium carbonate, sodium carbonate or potassium carbonate.
 5. Themethod as defined in claim 1 wherein the reaction of the vinyl bromideand cyclizing agent is carried out at a temperature of within the rangeof from about 25° C. to about 80° C.
 6. The method as defined in claim 1wherein the vinyl bromide has the structure ##STR38##
 7. The method asdefined in claim 6 wherein the final product has the struture ##STR39##8. The method as defined in claim 7 wherein in the final product one ofR¹ and R² is lower alkyl and the other is H.
 9. The method as defined inclaim 7 wherein in the final product one of R¹ and R² is pentyl and theother is H, m is 1 and n is
 2. 10. The method as defined in claim 1wherein the cyclizing agent is cesium carbonate in a dioxane solvent.11. A method for preparing an oxazole compound having the structure##STR40## including all stereoisomers thereof, wherein m is 1, 2 or 3;nis 0, 1, 2, 3 or 4; (CH₂)_(n) is unsubstituted or is substituted withone or two alkyl groups; R¹ is lower alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, saturated heterocycle, or aromatic heterocycle; and R²is hydrogen, lower alkyl, aryl, or aralkyl, or R¹ and R² together withthe N to which they are linked form a 5- to 8- membered ring; and whichcomprises treating an amide of the structure ##STR41## with a brominesource at a reduced temperature, and then with an organic base to form avinyl bromide of the structure ##STR42## and treating the vinyl bromidewith a cyclizing agent which has the formula

    M.sub.2 CO.sub.3

wherein M is a Group 5 or 6 alkali metal or a Group 5 or 6 alkalineearth metal to form the desired oxazole compound.
 12. The method asdefined in claim 11 wherein the cyclizing agent is a metal carbonate.13. The method as defined in claim 11 wherein the bromine source isbromine and the reaction with bromine is carried out at a temperature ofwithin the range of from about -80° C. to about -25° C.
 14. The methodas defined in claim 11 wherein the cyclizing agent is employed with aGroup 2 to 4 alkali metal carbonate.
 15. The method as defined in claim11 wherein the starting amide has the structure ##STR43##
 16. The methodas defined in claim 11 wherein the final product has the struture##STR44##
 17. The method as defined in claim 11 wherein the cyclizingagent is cesium carbonate.
 18. A method for preparing an oxazolecompound having the structure ##STR45## including all stereoisomersthereof, wherein m is 1, 2 or 3;n is 0, 1, 2, 3 or 4; (CH₂)_(n) isunsubstituted or is substituted with one or two alkyl groups; R¹ islower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, saturatedheterocycle, or aromatic heterocycle; and R² is hydrogen, lower alkyl,aryl, or aralkyl, or R¹ and R² together with the N to which they arelinked form a 5- to 8- membered ring; and which comprises treating achloromethyl amide of the structure ##STR46## with1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form an amide of thestructure ##STR47## treating the so-formed amide with a bromine sourceat a reduced temperature and then with an organic amine to form a vinylbromide of the structure ##STR48## and treating the vinyl bromidecompound with a cyclizing agent has the formula

    M.sub.2 CO.sub.3

where M is a Group 5 or 6 alkali metal or a Group or 6 alkaline earthmetal, to form the desired oxazole compound.
 19. The method as definedin claim 18 wherein the cyclizing agent is a metal carbonate.
 20. Themethod as defined in claim 18 wherein the bromine source is bromine andthe reaction with bromine is carried out at a temperature of within therange of from about -80° C. to about -25° C.
 21. The method as definedin claim 18 wherein the cyclizing agent is employed with a Group 2 to 4alkali metal carbonate.
 22. The method as defined in claim 18 whereinthe cyclizing agent is cesium carbonate.
 23. The method as defined inclaim 18 wherein the starting amide has the structure ##STR49##
 24. Themethod as defined in claim 18 wherein the final product has the struture##STR50##
 25. A method for preparing an oxazole acid compound having thestructure ##STR51## including all stereoisomers thereof, wherein m is 1,2 or 3;n is 0, 1, 2, 3 or 4; (CH₂)_(n) is unsubstituted or issubstituted with one or two alkyl groups; R¹ is lower alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, saturated heterocycle, or aromaticheterocycle; and R² is hydrogen, lower alkyl, aryl, or aralkyl, or R¹and R² together with the N to which they are linked form a 5- to 8-membered ring; and which comprises treating a vinyl bromide of thestructure ##STR52## with a cyclizing agent which has the formula M₂ CO₃wherein M is a Group 5 or 6 alkali metal or a Group or 6 alkaline earthmetal, to form the desired oxazole ester compound, treating the oxazoleester with an alkali metal hydroxide to form the corresponding alkalimetal salt, and treating the alkali metal salt with an acid to form thecorresponding acid product.
 26. The method as defined in claim 25wherein the cyclizing agent is cesium carbonate.
 27. A method forpreparing an oxazole acid salt compound having the structure ##STR53##including all stereoisomers thereof, wherein m is 1, 2 or 3;n is 0, 1,2, 3 or 4; (CH₂)_(n) is unsubstituted or is substituted with one or twoalkyl groups; R¹ is lower alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, saturated heterocycle, or aromatic heterocycle; and R²is hydrogen, lower alkyl, aryl, or aralkyl, or R¹ and R² together withthe N to which they are linked form a 5- to 8- membered ring; and whichcomprises treating a vinyl bromide of the structure ##STR54## with acyclizing agent which has the formula

    M.sub.2 CO.sub.3

wherein M is a Group 5 or 6 alkali metal or a Group 5 or 6 alkalineearth metal, to form the desired oxazole ester compound, and treatingthe oxazole ester with an alkali metal hydroxide to form thecorresponding alkali metal salt.
 28. The method as defined in claim 27wherein the cyclizing agent is cesium carbonate.